Once myocardium dies during a heart attack, it is replaced by scar tissue over the course of several weeks. The size, location, composition, structure, and mechanical properties of the healing scar are all critical determinants of the fate of patients who survive the initial infarction. While the central importance of scar structure in determining pump function and remodeling has long been recognized, it has proven remarkably difficult to design therapies that improve heart function or limit remodeling by modifying scar structure. Many exciting new therapies are under development, but predicting their long-term effects requires a detailed understanding of how infarct scar forms, how its properties impact left ventricular function and remodeling, and how changes in scar structure and properties feed back to affect not only heart mechanics but also electrical conduction, reflex hemodynamic compensations, and the ongoing process of scar formation itself. In this article, we outline the scar formation process following a myocardial infarction, discuss interpretation of standard measures of heart function in the setting of a healing infarct, then present implications of infarct scar geometry and structure for both mechanical and electrical function of the heart and summarize experiences to date with therapeutic interventions that aim to modify scar geometry and structure. One important conclusion that emerges from the studies reviewed here is that computational modeling is an essential tool for integrating the wealth of information required to understand this complex system and predict the impact of novel therapies on scar healing, heart function, and remodeling following myocardial infarction. © 2015 American Physiological Society. Compr Physiol 5:1877-1909, 2015.

Physiological Implications of Myocardial Scar Structure

Gender-associated differences in the development of cardiovascular diseases have been described in humans and animals. These differences could explain the low incidence of cardiovascular disease in women in the reproductive period, such as stroke, hypertension, and atherosclerosis. The cardiovascular protection observed in females has been attributed to the beneficial effects of estrogen on endothelial function. Besides estrogen, sex hormones are able to modulate blood pressure by acting on important systems as cardiovascular, renal, and neural. They can have complementary or antagonistic actions. For example, testosterone can raise blood pressure by stimulating the renin-angiotensin-aldosterone system, whereas estrogen alone or combined with progesterone has been associated with decreased blood pressure. The effects of testosterone in the development of cardiovascular disease are contradictory. Although some researchers suggest a positive effect, others indicate negative actions of testosterone. Estrogens physiologically stimulate the release of endothelium-derived vasodilator factors and inhibit the renin-angiotensin system. Although the cardioprotective effects of estrogen are widely appreciated, little is known about the effects of progesterone, which is commonly used in hormone replacement therapy. Progesterone has both vasodilatory and vasoconstrictive effects in the vasculature, depending on the location of the vessel and the level of exposure. Nevertheless, the mechanisms through which sex hormones modulate blood pressure have not been fully elucidated. Therefore, the characterization of those could lead to a better understanding of hypertension in women and men and perhaps to improved forms of therapy.

https://www.degruyter.com/downloadpdf/j/hmbci.2014.18.issue-2/hmbci-2013-0048/hmbci-2013-0048.xml

Sex hormones in the cardiovascular system.

The heart is vital for biological function in almost all chordates, including humans. It beats continually throughout our life, supplying the body with oxygen and nutrients while removing waste products. If it stops, so does life. The heartbeat involves precise coordination of the activity of billions of individual cells, as well as their swift and well-coordinated adaption to changes in physiological demand. Much of the vital control of cardiac function occurs at the level of individual cardiac muscle cells, including acute beat-by-beat feedback from the local mechanical environment to electrical activity (as opposed to longer term changes in gene expression and functional or structural remodeling). This process is known as mechano-electric coupling (MEC). In the current review, we present evidence for, and implications of, MEC in health and disease in human; summarize our understanding of MEC effects gained from whole animal, organ, tissue, and cell studies; identify potential molecular mediators of MEC responses; and demonstrate the power of computational modeling in developing a more comprehensive understanding of ‟what makes the heart tick.ˮ.

https://journals.physiology.org/doi/pdf/10.1152/physrev.00036.2019

Cardiac Mechano-Electric Coupling: Acute Effects of Mechanical Stimulation on Heart Rate and Rhythm

Testosterone enhances functional recovery after stroke through promotion of antioxidant defenses, BDNF levels and neurogenesis in male rats.

The second messengers, cAMP and cGMP, regulate a number of physiological processes in the myocardium, from acute contraction/relaxation to chronic gene expression and cardiac structural remodeling. Emerging evidence suggests that multiple spatiotemporally distinct pools of cyclic nucleotides can discriminate specific cellular functions from a given cyclic nucleotide-mediated signal. Cyclic nucleotide phosphodiesterases (PDEs), by hydrolyzing intracellular cyclic AMP and/or cyclic GMP, control the amplitude, duration, and compartmentation of cyclic nucleotide signaling. To date, more than 60 different isoforms have been described and grouped into 11 broad families (PDE1-PDE11) based on differences in their structure, kinetic and regulatory properties, as well as sensitivity to chemical inhibitors. In the heart, PDE isozymes from at least six families have been investigated. Studies using selective PDE inhibitors and/or genetically manipulated animals have demonstrated that individual PDE isozymes play distinct roles in the heart by regulating unique cyclic nucleotide signaling microdomains. Alterations of PDE activity and/or expression have also been observed in various cardiac disease models, which may contribute to disease progression. Several family-selective PDE inhibitors have been used clinically or pre-clinically for the treatment of cardiac or vascular-related diseases. In this review, we will highlight both recent advances and discrepancies relevant to cardiovascular PDE expression, pathophysiological function, and regulation. In particular, we will emphasize how these properties influence current and future development of PDE inhibitors for the treatment of pathological cardiac remodeling and dysfunction.

/pdf/targeting-cyclic-nucleotide-phosphodiesterase-in-the-heart-4w2zaden5x.pdf

Targeting cyclic nucleotide phosphodiesterase in the heart: therapeutic implications.

Testosterone replacement therapy promotes angiogenesis after acute myocardial infarction by enhancing expression of cytokines HIF-1a, SDF-1a and VEGF.

Neuroprotective effects of testosterone upon cardiac sympathetic function in rats with induced heart failure.

Interventional effect of valsartan on expression of inducible cAMP early repressor and phosphodiesterase 3A in rats after myocardial infarction.

https://www.onlinecjc.ca/article/S0828-282X(11)00135-8/pdf

Regional Differential Expression of TREK-1 at Left Ventricle in Myocardial Infarction

Mechanosensitive channels have been determined to work as transducers of mechanoelectric feedback in the heart, which is associated with the generation of arrhythmias Recent studies have investigated the role of the cytoskeleton in ion channels control This study explored the ability of taxol to inhibit stretch-induced electrophysiological alterations in the ischemic myocardium Thirty-two Wistar rats were randomly divided into four groups: normal control group (n=9), taxol group (n=7), myocardial infarction (MI) group (n=9), and MI+taxol group (n=7) After Langendorff perfusion, the isolated hearts were stretched for 5 s by balloon inflation to 02 or 03 mL The effects of stretching on 90% monophasic action potential duration (MAPD(90)), premature ventricular beats (PVB), and ventricular tachycardia (VT) were observed for 30 s Stretching increased MAPD(90) in both the normal control and MI groups, but MAPD(90) increased more in the MI group for the same degree of stretch Taxol (5 mumol L(-1)) had no effect on MAPD(90) under baseline, unstretched conditions, but MAPD(90) in the taxol group was slightly increased after stretching compared with the normal control group (P>005) However, taxol reduced MAPD(90) in infarcted myocardium (P<005 at DeltaV=03 mL) The incidences of PVB and VT in the MI group were higher than in the normal control group (both P<001) Taxol had no effect on the occurrence of arrhythmias in normal myocardium, but it inhibited PVB and VT in infarcted hearts (both P<001) Thus changes in MAPD and the occurrence of arrhythmias caused by mechanical stretching of the myocardium could be inhibited by taxol in isolated rat hearts during AMI, indicating the involvement of tubulin in mechanoelectric feedback in AMI

Rongsheng Xie

Papers

Testosterone replacement therapy promotes angiogenesis after acute myocardial infarction by enhancing expression of cytokines HIF-1a, SDF-1a and VEGF.

Neuroprotective effects of testosterone upon cardiac sympathetic function in rats with induced heart failure.

Interventional effect of valsartan on expression of inducible cAMP early repressor and phosphodiesterase 3A in rats after myocardial infarction.

Regional Differential Expression of TREK-1 at Left Ventricle in Myocardial Infarction

Taxol inhibits stretch-induced electrophysiological alterations in isolated rat hearts with acute myocardial infarction.